Terra Sigillata

Reuters and Bloomberg reported earlier this week on an ongoing patent battle (read: pissing match) between Pfizer and Eli Lilly & Co. relating to their erectile dysfunction drugs Viagra and Cialis, respectively.

i-c45a03a82470db4e8e4cc3c9a7bdd758-Goat-thumb-175x169-41239.jpgA US Patent and Trademark Office (USPTO) appeals committee has ruled that an element of Pfizer’s patent on sildenafil, the active chemical in Viagra, is invalid because the drug is insufficiently different from a traditional Chinese medicine called Yin Yang Huo or horny goat weed.

At issue is Pfizer’s claim to a method for treating male erectile dysfunction. The patent appeals panel ruled that the method did not constitute a new invention because of the precedent set by Yin Yang Huo. Moreover, the board ruled that chemicals found in the herbal medicine act by the same mechanism as sildenafil by inhibition of an enzyme called phosphodiesterase-5 (PDE5). Therefore, the panel ruled, “the patent claim was the next logical step up from using the herb.”

I’m not an expert in law but there are untold number of traditional remedies touted for all sorts of sexual enhancement, none of which have the convincing efficacy of the prescription PDE5 inhibitors. We may call the condition “erectile dysfunction” today and the idea of treating it may have existed for centuries but having a compound that can actually do anything about it is an invention. However, I can see the fine distinction if Pfizer claimed that the idea of treating erectile dysfunction was an invention.

You lawyers out there can weigh in but this sounds like a bunch of posturing for market share: worldwide Viagra sales were $2 billion USD last year.

But what is this horny goat weed and why is it being singled out?

Horny goat weed is the colloquial name for any number of species of plants in the Epimedium genus. Most medicinal plant accounts describe some variation on the theme that a Chinese goat herder observed an increase in mating behavior among his flock while grazing on the plant. According to North Carolina State University Department of Horticulture webpage, it grows as a deciduous perennial ground cover in USDA Zones 6, 7, and 8.

Icariin and sildenafil.gifThe active compound in horny goat weed is a flavonol called icariin. As shown above, icariin (left) is about as can be from sildenafil (right). Moreover, icariin is a poor inhibitor of PDE5, with a IC50 value of 5.9 μM, making it about 80-fold less potent than sildenafil (IC50 = 75 nM) (J Nat Prod 2008; 71:1513-1517.)

And remember: that’s the purified compound in an isolated enzyme assay. Let’s take a look at the plant extract itself, the product sold on the internet and in health food stores as horny goat weed.

Horny Goat Weed Fig 4 Int J Impot Res.jpgThis figure comes from a 2006 paper in the International Journal of Impotence Research (2006; 18:335-342) where an extract of a specifically-selected Epimedium plant was extracted and partially purified, then tested relative to sildenafil in a tissue preparation of rabbit corpus cavernosum (the crucial penile vasculature). The extract, EP-20 was tested here for its ability to increase the levels of the second-messenger molecule cGMP in response to the nitric oxide donor, sodium nitroprusside (SNP). Erectile dysfunction agents acts to inhibit the degradation of cGMP, causing the corpus cavernosum to relax and increase blood flow to the penis.

The EP-20 extract does indeed increase SNP-stimulated cGMP concentration over SNP alone, but it tops out at about 1/10 the levels stimulated by sildenafil (note the broken y-axis for scale). More importantly, the concentrations of horny goat weed extract are tremendously high: 0.1 and 0.3 mg/mL. A direct comparison with sildenafil is difficult because it is a pure compound while the EP-20 horny goat weed extract is a mixture of all the chemicals that occur in the plant.

The take-home messages?:

  • The active constituent of horny goat weed, icariin, bears no structural similarity to sildenafil.
  • Sildenafil is 80 times more potent than icariin in inhibiting phosphodiesterase-5
  • Horny goat weed extract must be used at unbelievably high concentrations – far more than can be achieved in the bloodstream – to cause only 1/10th the effectiveness of sildenafil in a rabbit penile blood vessel model.

So, horny goat weed is far from stiff competition for a prescription PDE5 inhibitor like sildenafil. Yes, it has the potential to target an animal model of penile vasculature in a manner similar to sildenafil but it is unlikely to occur in a real-life scenario. However, there have been no head-to-head clinical trials of horny goat weed extract and sildenafil.

Going back to the Pfizer and Eli Lilly spat, there is really little comparison between horny goat weed and the active compound in Viagra.

And as for anyone thinking that horny goat weed might be a more cost-effective substitution for Viagra? You’re probably better off buying a dietary supplement intentionally adulterated with the prescription drugs.

Comments

  1. #1 Guzzo
    February 18, 2010

    I’m pretty sure that this used to be named “Horny Old Goat Weed”, but I could be wrong.

  2. #2 daedalus2u
    February 18, 2010

    Claim 24 should be rejected. It should never have been allowed in the first place.

    http://www.google.com/patents?id=XugKAAAAEBAJ&printsec=claims&zoom=4#v=onepage&q=&f=false

    If it was allowed, it would authorize Pfizer to block the sale of horny goat weed because HGW containes a PDE inhibitor, and is used to treat impotence.

    This isn’t at all close.

  3. #3 Blake
    February 18, 2010

    If you rotate one of the molecules 180 degrees you would find a lot of similarities in carbon structure and moieties.

    A couple interesting animal studies are out there too. (http://www.ncbi.nlm.nih.gov/pubmed/2014158, http://www.ncbi.nlm.nih.gov/pubmed/17169663)The first one comparing icariin and sildenafil suggests that 1) icariin 10mg/kg has some predictable effect, and this dose is in the range of an achievable human dose; 2) icariin low dose may work better than high dose and 2) effects of icariin may extend beyond PDE inhibition. The second study shows that icariin is probably about as potent as zaprinast, which is probably about 10x less potent than sildenafil.

    The more I look at the molecules, the more sildenafil starts to look like an icariin analog.

  4. #4 Ian Musgrave
    February 18, 2010

    Wait a minute, let me get this straight. The patent on Sildenafil, a compound that was rationally designed to specifically inhibit PDE (1) and developed prior to 1996 was invalidated because of a structurally unrelated component of a herbal extract that wasn’t even shown to act on the cGMP/NO system before 2001? (2)

    Pfizer is supposed to have time travel? The fact that a herbal treatment alleged to help sexual function would turn out, 5 years after the sildenafil patent had been granted (and the concept of PDE5 inhibitors as treatment for erectile dysfunction wide spread) to have effects on PDE5 could not possibly count as prior art. If so, the 1983 demonstration that the PDE inhibitor papaverine could produce erections would have invalidated the sildenafil patent.

    The patent boards ruling is patently rubbish. How can sildenafil “logically flow” from a compound that wasn’t even known to really work, let alone known to inhibit PDE?

    (1)Nicholas K. Terrett, Andrew S. Bell, David Brown and Peter Ellis. Sildenafil (VIAGRATM), a potent and selective inhibitor of type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction. Bioorganic & Medicinal Chemistry Letters
    Volume 6, Issue 15, 6 August 1996, Pages 1819-1824
    (2)Xin ZC. Kim EK, Tian ZJ, Lin GT, Guo YL. Icariin on relaxation of corpus cavernosm smooth muscle. Chin Sci Bulle 2001; 46: 485-9.

  5. #5 Ian Musgrave
    February 18, 2010

    #3 Blake wrote:

    The more I look at the molecules, the more sildenafil starts to look like an icariin analog.

    No, not at all. You can stick the benzofuran of the flavonol on top of the methylxanthine moiety of the sildenafil, but the charge distribution and 3D structure is all wrong, the flavonol has these huge sugar moieties which have the wrong charge and stick out in places that should inhibit binding, it lacks the bulky positively charged ring that fits into the PDE5 specific binding pocket. (I have the an image of the 3D structural overlay if anyone want to see them).

    Looking at it, icariin does not scream either methylxanthine mimetic or “PDE inhibitor”, in fact I would guess it would be worthless. However, flavonols and flavinoids have a habit of doing things we don’t expect, such as resveratrol being a very decent cannaboid receptor anatgonist, despite looking nothing like cannabinoids of the synthetic antagonists.

    Even so, the fact that icariin was only shown to act on the NO/cGMP system (not even showing PDE5 activity) five years after the first publication on sildenafil being a PDE inhibitor, there’s no way icariin sould invalidate the patent.

  6. #6 Abel Pharmboy
    February 18, 2010

    Ian – thanks for the superb point. I was thinking about the “time travel” thing when trying to find papers on icariin and PDE5. You state it very eloquently.

    I have to admit not having an understanding of US patent law like daedalus4u, but Jim Edwards at BNET had this to say in his take on the rejection of claim 24:

    The PTO concluded:

    … we sustain the rejections of claim 24 under 35 U.S.C. § 102(b) as anticipated by any of [the horny goat weed studies by] Bensky, Hsu, Chang, and Yin. The Yin Yang Huo references disclose oral administration of a selective PDEV inhibitor, i.e., icariin, in an amount effective to treat ED.

    If this is the standard for rejecting drug patents then we’ll all be enjoying a vast range of cheap generic drugs very soon indeed.

  7. #7 Abel Pharmboy
    February 18, 2010

    Ian, our comments 5 and 6 crossed in the ether. I was going to ask you for your take on the structures because the stereochemistry and the sugars throw a wrench into the works.

    I’d love to see the 3D superimposition. Could you post a link to the figure here or e-mail it and I’ll put it up?

  8. #8 Ian Musgrave
    February 18, 2010

    Abel, I’ve just emailed overlay images to you.

  9. #9 Ian Musgrave
    February 18, 2010

    The PTO concluded:
    … we sustain the rejections of claim 24 under 35 U.S.C. § 102(b) as anticipated by any of [the horny goat weed studies by] Bensky, Hsu, Chang, and Yin. The Yin Yang Huo references disclose oral administration of a selective PDEV inhibitor, i.e., icariin, in an amount effective to treat ED.

    Well after 1996, none of these references show oral administration for anything, let alone erectile dysfunction, before 1999 (well, there’s a paper in 1995 on renal function in “Yang-deficiency” model mice, but that’s not ED).

  10. #10 daedalus2u
    February 19, 2010

    They didn’t invalidate the “viagra patent”, they invalidated a single claim in the patent, a claim which was not about viagra at all, but about all phosphodiesterase inhibitors.

    Horny goat weed contains a phosphodiesterase inhibitor, horny goat weed is given orally, horny goat weed is used to treat impotence. Horny goat weed is covered by claim 24.

    If claim 24 was upheld, then Pfizer could start demanding royalties from people selling horny goat weed, even people that have been growing and selling horny goat weed for centuries.

    I appreciate that Pfizer isn’t trying to get royalties from horny goat weed, but from other pharma companies that are selling synthetic PDE5 inhibitors that are different than sildenafil. I appreciate that blocking other pharma companies from doing that is worth billions to Pfizer. Unfortunately for Pfizer there is no basis for doing so.

  11. #11 Ian Musgrave
    February 20, 2010

    Also Commented on over at the “Icariin from horny goat weed is structurally unrelated to sildenafil (Viagra®)” post.

    Now I am not a patent lawyer either (even though I am an author on a patent, Method of controlling damage mediated by alpha, beta-unsaturated aldehydes, which has singularly failed to bring my co-authors and I fame fortune and research funding), but I still cannot see how, for the life of me, the fact that horny goatweed is used to treat erectile dysfunction has any bearing on claim 24.

    Until 2001, 5 years after the patent was lodged there was no evidence that either horny goatweed or icariin had any effect on the NO/cGMP system, let alone the PDE5 enzyme.

    As an example, look at the herb Yohimbe, it’s used as a treatment for erectile dysfunction, and you could say the Pfizers’ patent clause 24 was invalid because Yohimbe treats erectile dysfunction. But Yohimbine, the active ingredient of Yohimbe, acts in a completely different manner (it’s an alpha-adrenoceptor blocker).

    The point is that clause 24 is a clause about selective cGMP PDE inhibitors, not “anything that can treat erectile dysfunction in anyway imaginable”. You can quite legitimately say clause 24 is too broad (but Pfizer hasn’t stomped on any other selective cGMP inhibitors like tadalafil or vardenafil etc.). But that’s the argument that should be used, not a spurious appeal to a herbal extract whose mechanism of action wasn’t known even in outline until 5 years after the patent was filed.

  12. #12 Blake
    February 22, 2010

    Great discussion and thanks for the 3D structures.. apparently the rejection of the claim was due to the plant and its use being found in the prior art.

    “But the judges were unconvinced, saying it was undisputed that the herb was orally administered, that it contained the purported aphrodisiac ingredient icariin and that the prior art disclosed oral administration of the herb in an amount effective to treat erectile dysfunction.” http://www.law360.com/articles/149895

    Im thinking this type of precedent could make it difficult to develop strong patents on drugs based (however loosely) on traditional ethnobotanical use.

  13. #13 Ian Musgrave
    February 22, 2010

    Daedelus2u wrote

    I appreciate that Pfizer isn’t trying to get royalties from horny goat weed, but from other pharma companies that are selling synthetic PDE5 inhibitors that are different than sildenafil. I appreciate that blocking other pharma companies from doing that is worth billions to Pfizer.

    But they haven’t. There are at lest 3 other PDE5 inhibitors out there right now that went to the market years ago and are now well established competitors. If Pfizer were going to enforce their broad patent as implied in clause 24, they would have already blocked Vardenafil and Tadalafil when they were released onto the market years ago.

  14. #14 sildenafil
    March 5, 2010

    I’d love to see the 3D superimposition. Could you post a link to the figure here or e-mail it and I’ll put it up?

  15. #15 daedalus2u
    March 5, 2010

    Ian, I didn’t know that Pfizer had not tried to block other PDE ID drugs from being sold. What that tells me is that they have a savvy patent department and wouldn’t risk jeopardizing their valuable patent by bringing crap lawsuits that they were going to lose. A patent with an invalid claim is more valuable even if that claim is never tested than a patent with a claim that has been invalidated.

    The news report does seem to indicate that it was Pfizer that brought the suit. “The claims came under contention as part of a patent infringement lawsuit Pfizer filed against Eli Lilly and Co, which makes the rival drug Cialis.”

    Some companies (probably most) might decide that even when they are very sure that claim 24 is invalid, that the business risk of suing to have it invalidated isn’t worth it. Pfizer has deep pockets. They could spend tens of millions defending a bogus patent claim and never miss it. It still becomes a crap shoot as to how a judge will rule, a judge who may not understand the science that well.

    A company could sell a PDE ID drug and be confident that because claim 24 is invalid that if Pfizer sues them, that claim 24 will be ruled invalid and they will be vindicated. If they guess wrong, and claim 24 is ruled valid, then they are liable for triple damages.

    I think the lawsuit isn’t really about issues of law. They are very clear cut in this case. I think it is about spin and how the spin affects the stock prices and drug sales. I would expect that both Viagra and Cialis had increased sales from the publicity due to this lawsuit.

    Blake, I don’t think this does inhibit using natural products as source material for developing new drugs. It does inhibit patenting natural products that have been in use for many years. Patenting is only to protect inventions, which are by definition something that has not been done before. If a natural product is already being used, there is no invention to use what is already in it.